3-aminoalkyl esters of 17-oxygenated androst-(an and 5-en)-3beta-ols



United States This invention relates to 3-aminoalkyl esters of 17-oxygenated androst--en-3-ols, 5,6-dihydro compounds corresponding thereto, and processes whereby these chemical compounds can be manufactured. More particularly, this invention relates to products of the formula and 5a,6-dihydro compounds identical therewith except for the absence of the 5(6) double bond, Z in the formula being representative of an optionally-alkylated amino radical; Alk an alkylene radical; and X is a carbonyl, hydroxymethylene, or alkanoyloxymethylene radical.

The symbol, Z, subsumes both the primary amino radical, --NI-I and secondary and tertiary amin radicals wherein one or two alkyl or hydroxyalkyl groupings are present. Among the latter groupings, especially lower alkyl and hydroxy(lower alkyl) radicals are preferred. Illustrative of lower alkyl radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, isohexyl, heptyl, octyl, and like --C,,H groupings wherein n represents a positive integer amounting to less than 9.

When the amino radical represented by Z is substituted by one or two alkyl'or hydroxylalkyl groupings, the substituent groupings can be'either discrete, as for example when Z designates a radical of the formula I lower alkyl 7 lower alkyl or they can be joined together directly or through oxygen or a second'nitrogen to compose cyclic amino radicals optimally comprising at least 4 carbon atoms. Illustrative of the cyclic amino radicals contemplated by Z are pyrrolidino, Z-methylpyrrolidino, 2,5-dimethylpyrrolidino, 3- methyl-4-ethylpyrrolidino, piperidino, 3-methylpiperidino, 2,6-dimethylpiperidino, morpholino, piperazino, 4-methylpiperazino, 4-hydroxyethylpiperazino, and like monovalent, 5- and G-membered heterocyclic groupings. The terminal ino in the radical names set forth denotes attachment of the radicals thus identified via nitrogen.

The alkylene radicals represented by Alk, like the alkyl and hydroxyalkyl groupings comprehended when Z represents a secondary or tertiary amino radical, are most de-, sirably of lower order. Typical of lower alkylene radicals are methylene, ethylene, trimethylene, 1,2-propylene, 2,2-dimethyl-1,3-propylene, tetramethylene, and homologous, bivalent, saturated, acyclic, straightor branchedchain hydrocarbon groupings embracive of fewer than 9 carbon atoms.

4 are i Both the hydroxymethylene and alkanoyloxymethylene radicals represented by X are desirably, though not neces sarily exclusively, those wherein the oxygenated methylene substituent is in beta configuration relative to the steroid nucleus; and the alkyl constituents of the alkanoyloxymethyl radicals comprehended.

are, again, optimally lower alkyl groupings.

Equivalent to the foregoing amine esters for purposes and 5u,6-dihydro salts corresponding, Z, Alk, and X being defined as before; Q representing hydrogen or a lower alkyl, hydroxy(lower alkyl), or lower alkenyl radical, as also such aralkyl radicals as benzyl, phenethyl, and naphthylmethyl; T representing one equivalent of an anionfor example, chloride, bromide, iodide, nitrate, phosphate, sulfate, sulfamate, methyl sulfate, ethyl sulfate, benzenesulfonate, toluenesulfonate, acetate, lactate, succinate, malate, maleate, tartrate, citrate, gluconate, ascorbate, benzoate, cinnamate, or the like-Which, in combination with the cationic portion of a salt aforesaid, is neither pharmacologically nor otherwise undesirable in physiological dosage; and y representing 1 except when Z comprises a piperazino or other dibasic amino radical, in which case y represents either 1 or 2. Y

The compounds of this invention are useful because of their valuable pharmacological properties. Thus, for example, they are anti-hormonal agents adapted, inter alia, to inhibit the effects of androgens on the secondary sex characteristics and counteract the tendency of cortisone to promote the spread of infection. Moreover, they'manifest selectively potent anti-cholesterologenic activity.

Manufacture of the claimed products proceeds by heating together, preferably in an inert solvent and with a catalyst such as sodium iodide present, a steroid of the formula O (ll-Alk-ii-O Patented -May 22, 1962- Z, Alk, and X in the formulas being defined as before. Alternatively, the l7fi-hydroxy products hereof derive from the corresponding 17-ones by sodium borohydride reduction in cold aqueous ethanol; and the l7-alcohols in turn, are converted to corresponding alkanoic acid esters by warming with alkanoic acid anhydride in pyridine.

Conversion of the amine bases hereof to corresponding acid addition salts is accomplished bysimple admixture of these compounds with either 1 or 2 equivalents of any of various inorganic and strong organic acids, the anionic portion of which conforms to T as hereinabove defined- The q aternary mmonium. o p nds compr h n by the invention are those derivedby contacting a claimed basewith an, organic ester of the formula Q' being identical with Q except that it never represents hydrogen and T having the same meaning assigned previously. Quaternization takes place in the temperature range between 25 and 100 centigrade, using an inert solvent such as chloroform, acetone, butanone, methanol, butanol, or the like as reaction medium. Quaternization is ordinarily completed in from 1 to 48 hours and is gone erally carried outv in a closed system if a lower alkyl halide-such as methyl ch1oride-is One of the reagents. Using methyl bromide, the manufacture of quaternary salt may be smoothly effected in butanone solution at 70 centigrade, the reaction time being approximately 45 minutes.

The following examples describe in detail compounds illustrative of the present invention and methods which have been devised for their manufacture; However, the invention is not to be construed as limited thereby, either in spirit or in scope, since it will be apparent to those skilled in the art of organic synthesis that many modifica-. tions, both of materials and of methods, may be prac-. ticed without departing from the purpose and intentof this disclosure. Throughout the examples hereinafter set forth, temperatures are given in degrees centigrade and relative amounts of materials in partsby weight, except as otherwise noted. Specific rotations refer to the D line of sodium, observations being made in chloroform 'solu.

4 of pyridine and 10 parts of acetic anhydride is let stand at room temperatures overnight, then partitioned between water and ether. The ethereal phase is separated, dried over anhydrous sodium sulfate, and stripped of solvent by distillation. The residue, recrystallized from a mixture of dichloromethane and ether, affords 17fi-acetoxy- 3,8-(3-pyrrolidinopropionyloxy)androst-S-ene, melting at 1595-163. The product has the formula 0 (nan.

is maintained with agitation at thev boiling point under reflux for 1 hour, then cooled and partitioned between Example 3 ether and water. The ether phase is separated, dried over pionyloxy)androst-S-en-17-one (preparableby the pro-- cedure of Example 5A hereinafter) in, parts of ethanol is. added, with agitation at 5'-10, a solution of 2 parts. of sodium borohydride in 24 parts of approximately ethanol. .Two minutes later; the reaction mixture is diluted with 3. volumes of ice water. The solid pre cipitate, filtered off and recrystallized from, acetone, atfords 3B-(3-pyrrolidinopropionyloxy) findrost-S-en-lZfi-ol, melting at 165-168 and having a-specific rotation of =46Q The product has. the formula 1 Example a 1 acejoxy f 35 (3 iayirolidihdbrbpionylafll artdrost-5-eyte'.-A solution of 2 parts of 3e-(3-pyrrolidinopropionyloxy)androst 5-enfl7B-o1in a mixture of 10 parts.

anhydrous, sodium sulfate, and stripped of solvent by distillation. The residue is 3,6-(chloroacetoxy) androst-S-enl7-one.

B. 3e- (dimethylaminoacetoxy androst-S -en-1 7-0ne.-- To approximately 65 parts of 3 8-(chloroacetoxy)androst- 5-en-l7-one in parts of tolueneat about 0 is added, with agitation, 10 parts of dimethylamine and 1 part of sodium iodide. The resultant mixture is transferred to a sealed vessel and maintained therein at 8Q for 5 hours, then cooled and consecutively washed with dilute aqueous sodium bicarbonate and water. It is then dried over anhydrous sodium sulfate and stripped of solvent by vacuum distillation. The residue is 3fl-(dimethylaminoaeetoxy)-- androst-5-en-l7-one, of the, formula 0 (CHahNOH -ii-O I Example 4 V A. 3,8 (3 chloropropionyloxy)androst 5 en 17-.

1 one.--To a solution of 20 parts of 'BB-hydroXyandrost-S- ,en-17-one' in 20 parts of 2,6-din1ethylpyridine is added,

with agitation, parts of benzene followed by 20 parts. of 3-chloropropionyl chloride. heated at the boiling, point under reflux with continued agitation for 1 hour, then poured onto ice. The benzene phase is separated and washed with water, then dried overanhyd fous sodium sulfate and finally stripped ofsolvent; by vacuum distillation. The residue is 3B-.(3-chloropro-. pionyloxy) androst-5-en-l7-one. r 7

- 13.313 (3 Diethylaminopropionyloxy)androst .i-v -17-on -.To a solution f ppro at y 3.5 Pa t of: Sfl-(S-chloropropionyltzxy)androst 5-en-l7-one in, 200.

parts of acetone, is added 4 parts of sodium iodide and 1 parts of .diethylamine. The; resultant mixture is heated at the, boiling point under reflux with agitation for 4 /2.

hours, then pouredinto. 3 volumes of dilute, aqueous sodi-. urn bicarbonate. The mixture thus obtainedis, extraeted The resultant mixture is.

5 with ether; The ether extract is washed with water and then dried over anhydrous sodium sulfate. Distillation of solvent affords, as the residue, 3B-(3-diethylaminopropionyloxy)androst-5-en-17-one, of the formula 'Exam pie 5 mo f . V v V O r onzom-h-o B. 3 3 (3 pyrrolidinopropionyloxy)andfost 5 en- 17 -ne hydrochloride-From a 2-propanolic solution of 33 (3 pyrrolidinopropionyloxy)andrst 5 a en 17- one, on acidification with concentrated hydrochloric acid, there precipitates 3B-(3-pyrrolidinopropiony1oxy)androst- 5-en-17-one hydrochloride, which melts at 217221 and has a specific rotation of +6.5.

C. 3,8 (3 pyrnolidinopropionyloxy)androst 5 en- 17-0ne methyl i0dide.-To a solution of 3 parts of 3;.8-(3- pyrrolidinopropionyloxy) androst-5-en-17-one in 20 parts of ether is added a solution of 3 parts of methyl iodide in 5 parts of ether. The product which precipitates is filtered off after 2 hours at room temperatures and dried in air. This material is 3 8-(3-pyrrolidinopropionyloxy)- androst-5-en-17-one methyl iodide melting at 202-2035".

D. 35 (3 pyrrolidinopropionyloxy)androst 5 en- 17-one benzyl chloride.--A solution of 3 parts of 35-(3- pyrrolidinopropionyloxy)androst-S-en-17-one and 1 part of benzyl chloride in parts of ether is heated to the boiling point under reflux, then stripped of solvent by distillation. The residue, recrystallized from water, affords 3,6-(3-pyrrolidinopropionyloxy)androst-S-en-I7-one benzyl chloride.

Example 6 separated and consecutively washed with dilute aqueous sodium bicarbonate and water, then dried over anhydrous sodium sulfate, and finally precipitated by addition of petroleum ether (B.P 63-71"). The solid product thrown down is filtered off and dried in air. It melts at 148-151" and has a specific rotation of +4.5 This material is 6 3B-(3-piperidinopropionyloxy)androst-5-en 17-one, of the formula 7 Example 7 3-p-(3-chlorobutyryloxy)androst-5-en-17-one.-To a solution of 50 parts of 3B-hydroxyandrost-5-en-17-one in 50 parts of 2,6-dimethylpyridine is added, with agitation at 5-10, 400 parts of benzene followed by 46 parts of 2- chlorobutyryl chloride. The resultant mixture is heated at the boiling point under reflux for 1 hour, then poured into 4volumes of ice water. The benzene phase is separated, washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residue i's' 3B-(3-chlorobutyryloxy)androst-5-en-l7- one.

B. (3 pyrrolidinobutyryloxy)androst 5 en- 17-one.To a solution of .85 parts of 3fi-(3-chlorobutyryloxy)androst-5-en-17-one in 500 parts of acetone is added 18 parts of pyrrolidine and 10 parts ofsodium iodide. The resultant mixture is heated with agitation at the boiling point for 4 /2 I hours, then poured into 3 volumes of ice water. The resultant mixture is extracted with dichloromethane. The dichloromethane extract is. separated, dried over anhydrous sodium sulfate, and stripped of sol-' vent by vacuum distillation. The residue is the desired 36-(3-pyrrolidinobutyryloxy)androst-5-en-17-one, of the formula v A. 3/3 (3 chloropropionyloxy) 50c androstan 17- one.-To a solution of 20 parts of 3/3-hydroxy-5a-androstan-17-one in 20 parts of 2,6-dimethylpyridine is added, with agitation, 160 parts of benzene followed by 20 parts of 3-chloropropionyl chloride. The resultant mixture is heated at room temperatures for 3 hours, then poured into 3 volumes of ice water. The benzene phase is separated, washed with water, dried over anhydrous sodium sulfate, and finally stripped of solvent by vacuum distillation. The residue is 35-(3-chloropropionyloxy)- Sa-androstan-17-one B. 3,8 (3 pyrrolidinopropionyloxy) 5a -andr0stan- 17-One.A mixture of parts of 3 3-(3-chloropropionyloxy)-5ot-androstan-17-one, 14 parts of sodium iodide, 28 parts of pyrrolidine, and 400 parts of acetone is heated at the boiling point under reflux with agitation for 4 hours, then cooled and partitioned between ether and dilute aqueous sodium carbonate. The ethereal phase is separated and washed with water. Upon evaporation of sol- Example 8 vent, there remains as the residue, 3fi-(3-pyrrolidinopro pionyloxy) -5 x-androstan-17-one, of the formula and u,6-dihydro compounds corresponding thereto,

in the formula being selected from the group consisting of di(lower alky1)amino, pyrrolidino, and piperidino rad: icals; Alk in the formula being a lower alkylene radical; and X in the formula being selected from the group consisting of carbonyl, p-hydroxymethylene, and p-(lower alkanoyDoxymethylene radicals.

f 2. 3{3-(3-pyrrolidinopropionyloxy)androst-5-en l7fi-ol. 3. A compound of the formula V v v t H30 5' wherein Alk is a loweralkylene radical.

4. 3,8 (3 diethylaminopropionyloxy)androst 5 en- 17-one.

5.- A compound of the formula 0 wherein Alk is a lower alkylene radical and p is a positive integer less than 3;

6. 3/3 (3 pyrrolidinopropionyloxy)androst 5 en- 17-one. 177. 36 (3 pyrrolidinopropionyloxy) 5a androstan- -one. 7

' References Cited in the file of this patent V e e e UNITED STATES PATENTS v 2,173,423 Miescher et a1. Sept. 19, 1939' 2,874,173 "Hogg et a1. Feb. 17, 1959 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA 